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J. Biol. Chem., Vol. 281, Issue 39, 28889-28900, September 29, 2006

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AUF1 Is Expressed in the Developing Brain, Binds to AT-rich Double-stranded DNA, and Regulates Enkephalin Gene Expression^*

Albert Dobi¹, Marianna Szemes¹, Cheol Lee, Miklos Palkovits, Francis Lim^¶, Andrea Gyorgy, Mark A. Mahan^||, and Denes V. Agoston²

From the Department of Anatomy, Physiology, and Genetics, School of Medicine, Uniformed Services University, Bethesda, Maryland 20814, National Institute of Mental Health, Bethesda, Maryland 20892, the ^¶Department of Biochemistry, University of New Mexico, Albuquerque, New Mexico 87131, and the ^||Department of Neurology, Columbia University, New York, New York 10027

During our search for transcriptional regulators that control the developmentally regulated expression of the enkephalin (ENK) gene, we identified AUF1. ENK, a peptide neurotransmitter, displays precise cell-specific expression in the adult brain. AUF1 (also known as heterogeneous nuclear ribonucleoprotein D) has been known to regulate gene expression through altering the stability of AU-rich mRNAs. We show here that in the developing brain AUF1 proteins are expressed in a spatiotemporally defined manner, and p37 and p40/42 isoforms bind to an AT-rich double-stranded (ds) DNA element of the rat ENK (rENK) gene. This AT-rich dsDNA sequence acts as a cis-regulatory DNA element and is involved in regulating the cell-specific expression of the ENK gene in primary neuronal cultures. The AT-rich dsDNA elements are present at 2.5 kb 5'upstream of the rat, human, and mouse ENK genes. AUF1 proteins are shown here to provide direct interaction between these upstream AT-rich DNA sequences and the TATA region of the rENK gene. Double immunohistochemistry demonstrated that in the developing brain AUF1 proteins are expressed by proliferating neural progenitors and by differentiating neurons populating brain regions, which will not express the ENK gene in the adult, suggesting a repressor role for AUF1 proteins during enkephalinergic differentiation. Their subnuclear distribution and interactions with AT-rich DNA suggest that in the developing brain they can be involved in complex nuclear regulatory mechanisms controlling the development- and cell-specific expression of the ENK gene.

Received for publication, November 3, 2005 , and in revised form, June 8, 2006.

^* This work was supported by grants from the Defense and Veterans Head Injury Program, Uniformed Services University of the Health Sciences intramural grant, and an NICHD grant from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Anatomy, Physiology, and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, B2036, Bethesda, MD 20814. Tel.: 301-295-9378; Fax: 301-295-1715; E-mail: vagoston{at}usuhs.mil.

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